title: Pharmacogenetic influence of GST polymorphisms on anthracycline-based chemotherapy responses and toxicity in breast cancer patients: a multi-analytical approach.
abstract: OBJECTIVE
  Chemotherapeutic drug treatment outcomes are genetically determined. Polymorphisms in genes encoding phase II drug metabolizing enzyme glutathione-S-transferase (GST) can possibly predict treatment outcomes, and can be of prognostic significance in breast cancer patients. The aim of this study was to determine the role of genetic variations in GST in predicting response to, and toxicity of, anthracycline-based chemotherapy in breast cancer patients.
  
  
  METHODS
  Two hundred and seven patients treated with anthracycline-based chemotherapy were genotyped for GSTM1 and GSTT1 deletion polymorphisms, and GSTP1 Ile105Val (rs1695), by polymerase chain reaction (PCR)/ PCR-restriction fragment length polymorphism (RFLP). Genetic variations were correlated with tumor response to neo-adjuvant chemotherapy (NACT) in 100 patients, and with chemo-toxicity in 207 who received adjuvant chemotherapy or NACT, using Chi-square and logistic regression. Higher order gene-gene interactions with treatment outcomes were characterized by multifactor dimensionality reduction (MDR) analysis.
  
  
  RESULTS
  In single-locus analysis, Ile/Val and Ile/Val+Val/Val genotypes of the GSTP1 Ile105Val (rs1695) polymorphism reached statistical significance with grade 2-4 anemia (P=0.019, P=0.027). On performing gene-gene interaction analysis, GSTM1 null-GSTP1 Ile/Val was significantly associated with response to NACT (P=0.032). On evaluating higher order gene-gene interaction models by MDR analysis, GSTM1 and GSTP1 Ile105Val; GSTM1 and GSTT1; and GSTT1 and GSTP1 Ile105Val showed significant association with treatment response, grade 2-4 anemia, and dose delay/reduction due to neutropenia (P=0.046, P=0.027, P=0.026), respectively.
  
  
  CONCLUSIONS
  Multi-analytical strategies may serve as a better tool for characterization of pharmacogenetic-based breast cancer treatment outcomes.
authors.affiliation: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli road, Lucknow, 226 014, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Tulsyan
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: Gaurav
authors.initials: G
authors.lastname: Agarwal
authors.forename: Punita
authors.initials: P
authors.lastname: Lal
authors.forename: Sushma
authors.initials: S
authors.lastname: Agrawal
authors.forename: Rama Devi
authors.initials: RD
authors.lastname: Mittal
authors.forename: Balraj
authors.initials: B
authors.lastname: Mittal
mesh_terms: D000328:Adult; D018943:Anthracyclines / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010597:Pharmacogenetics; D012150:Polymorphism, Restriction Fragment Length; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human